Biochemical studies in patients with autism spectrum disorder are indicative of the involvement of the serotonergic system in the etiology of the disorder. Specifically, selective serotonin reuptake inhibitors which target the serotonin transporter (SLC6A4, 5-HTT) were successfully used for treatment of autistic or concomitant symptoms such as repetitive behavior, language use or aggression. Several polymorphic loci in the 5-HTT gene, especially the HTTLPR, affect its expression or function.
Several studies report significant association of HTTLPR alleles with autism. However, the preferentially transmitted allele is almost equally divided between the short (S) or the long (L) allele in these studies. Furthermore, other studies report no association finding at all. Recently, it was shown for SNP rs25531 (A/G) located within HTTLPR that only the A variant of the L allele confers to high 5-HTT mRNA levels. The G variant within the L allele behaves like the low-expressing S allele. This may have lead to contradictory association results in the past.
To elucidate the impact of alleles at HTTLPR including the potentially functional SNP (rs25531), genotyping has been performed in a set of 180 complete trios from the German sample of patients with autism. In addition, the intron 2 VNTR and the rare gain-of-function coding mutation Ile425Val have been investigated.
We could not find association with either the HTTLPR alone or the haplotype HTTLPR-rs25531 performing TDT analysis. Furthermore, no association was evident for the intron 2 variant in our patient sample. Within the set of families no Ile425Val mutation could be found.
The negative results from our study of 180 German trios rule out any association between the serotonin transporter and the autism phenotype. But there may be other functional active polymorphic sites within 5-HTT that could confer liability to autism, which have not been tested here.